This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine dependence. Almost all subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. Pharmacokinetic approaches being studied include slow onset agonist substitution and enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. One component of this project is systematically evaluating the influence of dose and infusion rate on the effects of IV cocaine. Preliminary findings suggest that at least some of cocaine's psychological and physiological effects are both dose- and rate-dependent. Another component is evaluating effects of oral cocaine, a slow onset form of cocaine itself. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE), the primary cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Preclinical Pharmacology Laboratory and the National Institute on Aging, rats pretreated with BChE had less of a motor activity response to an IV cocaine challenge than did rats pretreated with saline. A pharmacodynamic approach being studied is use of combinations of medications, each acting on the same brain neurotransmitter system by a different mechanism, to enhance therapeutic effect while minimizing side- effects. Findings from a recently completed open-label trial with two dopaminergic medications, bromocriptine and bupropion, suggest that this combination is safe and has promise for the treatment of cocaine dependence. Future work will evaluate medication combinations in double- blind, controlled clinical trials. In animals, low calorie diets increase drug self-administration. These findings have clinical implications; e.g., some drugs of abuse suppress appetite, producing calorie deprivation. A recently begun outpatient study will evaluate the relationship between calorie deprivation produced by intentional dieting and cigarette smoking in patients attempting smoking cessation.